Summary

Eligibility
for people ages 45-80 (full criteria)
Location
at Sacramento, California and other locations
Dates
study started
estimated completion
Principal Investigator
by Barton L Wise, MD

Description

Summary

The primary objective of this study is to evaluate the safety and efficacy of two doses of CNTX-6970 for the treatment of pain related to OA of the knee compared to placebo. CNTX-6970 is being developed as a new treatment for chronic pain, including painful osteoarthritis of the knee.

Official Title

EN20-01: A 24 Week Study to Evaluate the Safety and Efficacy of CNTX-6970 in Subjects With Moderate to Severe Knee Osteoarthritis Pain.

Details

The study will employ a randomized, allocation-concealed, multicenter, placebo-controlled, multi-period crossover design (Schmid et al, 2018). This multi-period crossover randomized, controlled trial allows comparability and assessment of efficacy through repeated exposures within each subject to the active treatment and a control (placebo) in randomized sequence. Such multi-period crossover designs are ideal for treatments with rapid onset of action and short half-life such as the asset under study here. We have strived to minimize the complexity of this powerful design by using only 2 blocks with 2 periods each. The modest additional complexity of the proposed multi-period crossover design, compared to a parallel-groups design, is justified by the marked improvement in efficiency. The gains in efficiency afforded by the multi-period crossover design allow a substantial reduction in sample size without sacrificing statistical power. For example, our simulation experiments (with sample sizes ranging from 30 to 50, carryover effects ranging from 0 to 0.2, and an effect size of 0.4) indicated that the parallel design yields statistical power ranging from 0.20-0.25, whereas our proposed 2-block multi-period crossover design yields power ranging from 0.9-1.0. The trial will compare an active treatment vs. placebo. Each arm of the study will employ a multi-period crossover design with two blocks. Each block will consist of two treatment periods with each period lasting 6 weeks. Treatment assignments (active drug versus placebo) will be randomized for each patient to the two periods within each block. The period length of 6 weeks was chosen based on several considerations: (i) Most efficacious analgesic drugs demonstrate separation from placebo by 6 weeks; (ii) The decision to move CNTX-6970 forward to Phase 3 will require a clinically meaningful separation from placebo by 6 weeks; (iii) In this Phase 2 study, implementing a treatment block longer than 6 weeks would make the overall design more challenging and burdensome by extending the duration of overall testing beyond 6 months; (iv) Recent meta-analyses suggest that anti-inflammatory treatments such as NSAIDs reach peak effects on pain within a 4-week timeframe in patients with knee osteoarthritis, and multiple RCTs have specifically demonstrated efficacy for celecoxib at 2-6 weeks (Osani et al, 2020). The comparison with celecoxib is used to evaluate "assay sensitivity," i.e., to assess the study protocol's ability to demonstrate superiority of an established efficacious treatment (celecoxib 100mg BID). In this study, the placebo will consist of inactive tablets identical to the active treatment tablets. Treatment assignments (active drug versus placebo) will be randomized for each patient to the two treatment periods within each block

Keywords

Knee Osteoarthritis Osteoarthritis Osteoarthritis, Knee Celecoxib CNTX-6970

Eligibility

You can join if…

Open to people ages 45-80

  1. Individuals between 45 and 80 years of age (inclusive) at the time of the Screening Visit.
  2. Willing to use a mobile smart device during the study period. Individuals who do not have access to a mobile device will be provided with one for the duration of the study and trained in its use.
  3. Can understand the nature of the study and protocol requirements and is willing to comply with study drug administration requirements and discontinue prohibited concomitant medications.
  4. Provides written informed consent to participate in the study using a form approved by the institutional review board (IRB).
  5. Is capable of communicating with the site personnel, able to complete subject-reported outcome measures and can be reliably rated on assessment scales (in the opinion of the Site Investigator).
  6. Radiography of both knees with a posterior-anterior, fixed-flexion view taken during the Screening visit. The Index knee must show evidence of chronic OA with a K-L Grading Scale of 2 or 3. Such evidence will be provided by a central reading of the radiography of both knees from an expert radiologist of the CCC of EPPIC-Net.
  7. Moderate to severe pain in the Index knee associated with OA and stable for a minimum of 6 months prior to Screening in the opinion of the investigator.
  8. Confirmation of OA of the index knee: American College of Rheumatology (ACR) diagnostic criteria.
  9. Subjects must have failed 2 or more prior therapies. Failure is deemed to be inadequate relief in the opinion of the investigator. A therapy may be deemed to have been inadequate because of one or more of the following:
  10. unacceptable adverse events (AEs);
  11. inadequate response, or loss of response for chronic OA knee pain or
  12. pain in the index knee was minimally improved, not improved, or was worse and/or
  13. function, and/or stiffness in the index knee was minimally improved, not improved, or was worse
  14. medical condition resulting in contraindication to the standard of care appropriate to the severity of the index knee OA pain. "Therapies" include, but are not limited to, each of the following:
  15. nonsteroidal anti-inflammatory drugs (NSAIDs) (including topical), opioids, duloxetine, other systemic therapy, IA corticosteroids, IA viscosupplements
  16. physical therapy or bracing.
  17. . A mid-to-high level summed pain score (0-50) for the Index knee on the WOMAC-A pain subscale, which will be completed by the subject every 3 days (+/-1 day window) during the 14-day Screening period (5 times - screening days 0, 3, 6, 9, 12).Subject must complete all 5 screening WOMAC-A pain subscales. Criteria for pain intensity requirements are specified in Appendix IV: Unblinded Information. This is only available to unblinded study team members and will be assessed centrally. Additionally, eligibility per study pain intensity requirements will be confirmed by the CCC before a SAFER interview is scheduled.
  18. . Body mass index (BMI) of ≤ 37 kg/m2.
  19. . Females not of childbearing potential - defined as post-menopausal for at least 1 year, or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) - or practicing at least one of the following medically acceptable methods of birth control throughout the study period:
  20. Hormonal methods such as oral, implantable, injectable, or transdermal contraceptives for a minimum of 1 full cycle (based on the subject's usual menstrual cycle period) before study drug administration;
  21. Total abstinence from sexual intercourse since the last menses before study drug administration;
  22. Intrauterine device;
  23. Double barrier method (condoms, sponge, diaphragm, with spermicidal jellies or cream).
  24. . Male subjects capable of fathering a child must be willing to use barrier methods to avoid a pregnancy during the study. Male condoms with or without a spermicide coating are acceptable, as some women are allergic to spermicide.
  25. . Willing and able to understand the study requirements, abide by the study restrictions, complete the study procedures, independently record responses on the pain scales and make daily/weekly entries using the NEForm (section K1), and independently communicate meaningfully with study personnel.
  26. . Willing to refrain from illicit drug use during the study, and to have illicit drug testing at screening and at later time points, if illicit drug use is suspected during the study. Illicit drug use is defined as the use of any medication or substance that is outside the prescribed use of a medical professional, including medications that are prescribed but are not being used as prescribed. Cannabinoid use is exclusionary for this trial, regardless of reason for use.
  27. . Subjects must stop taking any current analgesic medications at the time of initial Screening and agree to take only the allowed rescue medication for OA knee pain (acetaminophen; 325mg x 2 tablets PO, QID, PRN) from the time of screening through study completion, and agree to use no topical medications for OA knee pain during the trial. Subjects must also stop taking any medication known to impact pain, even if taken for other indications, e.g. duloxetine for depression.
  28. . Complete the SAFER (State, Assessibility, Face and Ecological Validity and the Rule of the 3 Ps [persistent, pervasive, pathological]) interview and receive a passing score which will be administered by a remote telephone rater to confirm pain history with knee OA, eligibility per study pain intensity requirements, screening EMA score, and medication history.
  29. . The end of day EMA Alert #5 is completed on at least 5 out of the 7 days in the screening period. This is the last alert of the day and includes the daily NRS question.
  30. . Patient-reported daily NRS (for average pain over the last 24 hours) meets the criteria specified in "Appendix IV: Blinded Information" during the 7-day screening period. The algorithm is only available to unblinded study team members and will be assessed centrally. Additionally, screening NRS scores will be confirmed by the CCC before a SAFER interview is scheduled.
  31. . Completed at least 3/5 daily EMA alerts on days 6 and 7 of screening.

You CAN'T join if...

  1. Any form of joint replacement surgery of the index knee at any time, or open surgery of the index knee/knee joint in the past.
  2. Prior arthroscopic surgery of the index knee within 3 months of Screening.
  3. Any painful conditions of the index knee due to disease other than OA. For example, periarticular or referred pain involving the index knee, or from joint disease other than OA associated with the index knee.
  4. Other chronic pain anywhere in the body that is equal or greater in intensity or impairment than index knee pain or that requires the use of analgesic medications including, but not limited to, local painful areas, myofascial pain syndromes, fibromyalgia, genetic, metabolic abnormalities, hematologic or neuropathic pain, and any acute or chronic pain that may interfere with the study pain assessments by the subject.
  5. Secondary OA of the index knee due to acute or recurrent traumatic injury.
  6. Significant current or past instability (e.g., cruciate ligament tear or rupture or previous repair) or misalignment (>10 degrees varus or valgus) of the index knee.
  7. Documented history of neuropathic arthropathy in the knee.
  8. Imaging finding of bony fragmentation in the index knee (radiographic, computed tomography, or magnetic resonance imaging).
  9. Physical/occupational/chiropractic therapy for the lower extremities or acupuncture for the lower extremities within 30 days of Screening, or need for such therapy during the study.
  10. . Plans to have surgery, or other invasive procedures, or intra-articular (IA) injections while participating in the study.
  11. . Current use of opioids for any condition.
  12. . Use of pain medication (including non-steroidal anti-inflammatory drugs, medical cannabinoids/ CBD oil) less than 5 days before screening (acetaminophen is allowed) or any time throughout the study.
  13. . Corticosteroid injection in the index knee within 90 days of Screening or during study participation.
  14. . Received IA viscosupplementation (e.g., Synvisc®, Hyalgan®) within 90 days of Screening or any time during study participation.
  15. . History of clearly documented allergic reaction to celecoxib (Celebrex®), or to sulfa drugs.
  16. . Knee effusion requiring aspiration of the index or contralateral knee at time of screening.
  17. . Radiofrequency ablation (RFA) of the knee within 2 years prior to screening.
  18. . Presence of any medical condition or unstable health status that, in the judgment of the investigator, might adversely affect the safety of the subject or the conduct of the study, or negatively affect the resulting data, including chronic conditions that are likely to alter the rate of healing or are likely to result in safety complications unrelated to the study medication, or significant compromise to key organ systems.
  19. . Has a malignancy or has received treatment for malignancy at any time, with exception of resected basal cell carcinoma and squamous cell carcinoma of the skin within the past 5 years.
  20. . Ulcer or open wound anywhere in the region of the index knee.
  21. . Clinically significant abnormal laboratory results at the Screening Visit (in the opinion of the investigator), or significant organ disease that would put the subject at undue risk or affect the ability of the subject to participate in the trial.
  22. . Use of an investigational medication within 30 days of Screening, or 5 pharmacokinetic or pharmacodynamic half-lives (whichever is longer) or scheduled to receive such an agent while participating in the current study.
  23. . Has any of the following characteristics:
  24. active or historic substance use disorder within the previous year as defined by the Diagnostic and Statistical Manual for Mental Health Disorders, fifth edition, or
  25. urine drug screen is positive for a substance of abuse and participant is unable to provide a valid prescription from a medical professional.
  26. . Has moderate to severe depression or anxiety, as indicated by a score ≥ 11 on either subscale of the Hospital Anxiety or Depression Scale (HADS).
  27. . Has a positive pregnancy test at the Screening Visit.
  28. . Has ongoing litigation for workers compensation.
  29. . Known history or symptoms of long QT syndrome.
  30. . Male has a QRS interval >120 ms and QTcF ≥460 ms OR female has a QRS interval ≥120 ms and QTcF ≥480 ms at Screening or Baseline.
  31. . Has moderate to severe congestive heart failure (New York Heart Association [NYHA] class III and class IV).
  32. . Has a history of symptomatic cardiovascular disease.
  33. . K-L Grade 1 or 4 OA in the index knee.
  34. . Current therapy with any immunosuppressive therapy, including corticosteroids (>5 mg/day of prednisone).
  35. . Moderate to severe hepatic impairment at the Screening Visit, as defined by any of the following:
  36. AST and ALT values that are ≥1.5 times ULN; or
  37. Total bilirubin > 1.2 mg/dL; or
  38. Direct (conjugated) bilirubin > 0.3 mg/dL.
  39. . Moderate to severe renal impairment at the Screening Visit, as defined by either:
  40. An estimated glomerular filtration rate [eGFR] < 45 mL/min; or
  41. A serum creatinine level > 1.3 mg/dL).
  42. . Use of CYP3A4 inhibitors (e.g., grapefruit juice, omeprazole, pantoprazole) or CYP3A4 inducers (e.g., carbamazepine, rifampin, St. John's wort) within 7 days prior to the Baseline Visit or any time during study participation.
  43. . Use of CYP2C9 inhibitors (e.g., amiodarone, fluconazole) or CYP2C9 inducers (e.g. carbamazepine, rifampin, St. John's Wort) within 7 days prior to the Baseline Visit or any time during study participation.
  44. . Use of P-glycoprotein inhibitors (e.g., atorvastatin, azithromycin, carvedilol) within 7 days prior to the Baseline Visit or any time during study participation.
  45. . Is classified as a poor metabolizer via the CYP2C9 pathway as determined by genetic testing (CYP2C9 genotyping).
  46. . Has chronic or active infection(s) at the time of the Screening Visit.
  47. . Has clinically significant pulmonary disease such that medical treatment is required (e.g. COPD, asthma).
  48. . Has any of the following blood counts:
  49. Monocyte count < 0.5 % of white blood cells b. Platelet count , or i. Females (sex at birth): < 125,000/µL ii. Males (sex at birth): < 150,000/µL c. Hemoglobin: i.

Females (sex at birth): < 11.5 grams/dL ii. Males (sex at birth): < 13.0 grams/dL

Locations

  • University of California- Davis accepting new patients
    Sacramento California 95817 United States
  • VitaMed Research, LLC accepting new patients
    Palm Desert California 92260 United States

Lead Scientist at UC Davis

  • Barton L Wise, MD
    Professor, Rheumatology, Allergy, and Clinical Immunology. Authored (or co-authored) 41 research publications

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Maurizio Fava, MD
Links
Sign up for this study
ID
NCT05025787
Phase
Phase 2 Osteoarthritis Research Study
Study Type
Interventional
Participants
Expecting 150 study participants
Last Updated